The invention refers to novel piperazinylalkylthiopyrimidine derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active substance. The novel compounds can be employed mainly for the treatment of diseases that form due to disorders of the central nervous system.
More specifically, the invention refers to a novel piperazinylalkylthiopyrimidine derivative of the formula 
wherein
R1 represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkanoyl group or a di(C1-4 alkyl)amino(C1-4 alkyl) group,
R2 stands for a hydrogen atom or a benzyl group substituted by 1 to 3 substituent(s) selected from the group consisting of a C1-4 alkyl group, a C1-4 alkoxy group, a di(C1-4 alkyl)amino group, a hydroxy group and a halo atom,
n has a value of 2, 3 or 4,
and a pharmaceutically suitable acid addition salt thereof.
From Patent Application WO 97/16429, piperazinylalkylthiopyrimidine derivatives are known wherein the piperazine ring is substituted by a phenyl or a benzyl group at the nitrogen atom in position 4. The known compounds are suitable especially for the treatment of diseases of the central nervous system and have, for example, an outstanding anxiolytic activity. It is an important feature of the known compounds that they exert an effect at the serotonin receptors (5-HT2A, 5-HT2C). A considerable drawback of the known compounds resides in the fact that the compounds having the best anxiolytic effect metabolize very quickly in the living organism. Thus, the known compounds have a low biological utility that inhibits the development of drugs used in the clinical practice.
The aim of the invention is to prepare novel compounds that are effective mainly within the above field of biological action and more stable than the known compounds from the point of view of metabolism.
It was found that the above aim is achieved by the novel piperazinylalkylthiopyrimidine derivatives of the formula I having anxiolytic activity. However, the novel compounds do not exert any action on the serotonin receptors, and the metabolism thereof is not fast.
In the description, a C1-4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl or isobutyl group. Preferably, a C1-4 alkyl group is a methyl group or an isopropyl group.
A C1-4 alkoxy group is, primarily, a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group.
A halo atom is, in general, a fluoro, chloro or bromo atom, preferably a chloro atom or a fluoro atom.
Under a C1-4 alkanoyl group a formyl, acetyl, n-propanoyl, n-butanoyl group etc., preferably an acetyl group is meant.
The pharmaceutically suitable acid addition salts of the compounds of the formula I are the acid addition salts of the compounds formed with pharmaceutically suitable inorganic or organic acids including sulfonic acids. Preferred acid addition salts are the hydrogen halides such as hydrochlorides or hydrobromides, carbonates, hydrogen carbonates, sulfates, phosphates, acetates, fumarates, maleates, citrates, ascorbates and benzenesulfonates.
A preferred subgroup of the compounds of the invention consists of the compounds of the formula I and the pharmaceutically suitable acid addition salts thereof, wherein
R1 represents a hydrogen atom, a dimethylamino(C1-4 alkyl) group or a C1-4 alkanoyl group,
R2 is as defined in connection with formula I,
n has a value of 2 or 3.
The especially preferred piperazinylalkylthiopyrimidine derivatives of the invention consist of the compounds of the formula I, wherein
R1 represents a hydrogen atom or a dimethylamino(C1-4 alkyl) group,
R2 stands for a benzyl group substituted by a C1-4 alkoxy group, or a fluoro atom,
n has a value of 2,
and pharmaceutically suitable acid addition salts thereof.
In the definition of R2, conveniently, the C1-4 alkoxy group is in position ortho.
The compounds of the invention are prepared by reacting a 2-mercaptopyrimidine of the formula 
wherein R2 is as defined above, or an alkali metal salt thereof, with a haloalkylpiperazine of the formula 
wherein R1 and n are as stated above, HIg represents a halo atom, preferably a chloro or bromo atom, or an acid addition salt thereof, and, if desired, converting the compound of the formula I to a pharmaceutically suitable acid addition salt thereof, or liberating it from the acid addition salt thereof.
If desired, an obtained compound of the formula I can be transformed into another compound of the formula I. These additional transformations can be performed in a manner known per se. Thus, an obtained compound of the formula I, wherein R1 is a hydrogen atom, can be alkylated to obtain a compound of the formula I, wherein R1 stands for a C1-4 alkyl group. Compounds of the formula I, wherein R1 represents a dialkylaminoethyl group or an alkanoyl group, can be prepared through a similar additional transformation (alkylation or acylation). According to a further example of the additional transformation, a compound of the formula I, wherein R2 stands for an alkoxybenzyl group, is prepared by alkylating a compound of the formula I, wherein R2 is a hydroxybenzyl group, or a compound of the formula I, wherein R1 is a hydrogen atom, is prepared from the corresponding compound of the formula I, wherein R1 is a formyl group, and the latter group is removed by hydrolysis.
The process of the invention is carried out in an organic solvent or solvent mixture that is indifferent from the point of view of the reactants. For example, aliphatic alcohols such as methyl alcohol, isopropyl alcohol, dialkylamides, preferably dimethylformamide, water or a mixture thereof can be employed. The reaction of the compounds of the formulae II and III is performed either by using an alkali metal salt of the 2-mercaptopyrimidine of the formula II, or in the presence of an acid binding agent. For this purpose, preferably alkali metal carbonates such as sodium or potassium hydrogen carbonate, alkali metal hydroxides such as sodium or potassium hydroxide, alkali earth metal hydroxides such as calcium hydroxide, or tertiary amines such as pyridine, triethylamine or other trialkylamines can be used.
Preferably, the acid binding agent is potassium hydroxide, potassium carbonate or sodium carbonate.
Optionally, the reaction can be accelerated by means of a catalyst. Primarily, alkali metal halides or alkali earth metal halides (for example, potassium iodide, potassium fluoride, sodium bromide or calcium chloride) are used as the catalyst. Preferably, the reaction is carried out in the presence of potassium iodide catalyst.
The reaction is performed at a temperature between room temperature and the boiling point of the reaction mixture, depending on the reactivity of the starting substances. In an aqueous solution it is preferred to proceed at room temperature, in other cases a reaction temperature from 60 to 80xc2x0 C. is preferred. The reaction time is 2 to 20 hours, depending on the reactivity of the starting substances and the temperature employed.
The starting compounds of the formulae II and III can be used in an equimolar amount or the haloalkylpiperazine of the formula III is added to the reaction mixture in an excess of 10% at the most. The acid binding agent is used in an equimolar quantity, however, it can be employed even in a tenfold excess. When the starting substance is a salt of the mercapto compound, a lower amount of acid binding agent is needed, in general. Calculated for each mole of the 2-mercaptopyrimidine of the formula II, 0.1 to 0.2 moles of the catalyst is used, in general; preferably the reaction is performed in the presence of 0.1 moles of catalyst.
The reaction mixture is worked up in a manner known per se. It is preferred to separate the product as follows: the solution is separated from the precipitated inorganic salts by filtration, the filtrate is evaporated under reduced pressure, and the residue is crystallized from water or an organic solvent, or the precipitated product and inorganic salts are filtered together, and the inorganic salts are removed by washing with water. According to a further possibility, the reaction mixture is poured onto water to remove the inorganic salts, then the product is extracted or the precipitated product is filtered. If desired, the product is purified by known purification procedures such as recrystallization or chromatography.
The compounds of the formula I can be separated in the form of pharmaceutically suitable acid addition salts mentioned before, or the compounds of the formula I obtained as a base are converted to an acid addition salt by reacting the base in an indifferent solvent with the corresponding acid. From the acid addition salt, the base can be repeatedly liberated, then converted to another acid addition salt.
The starting compounds of the formula II are known from the literature. They can be prepared as described in Patent Application WO 97116429. Haloalkylpiperazines of the formula III are also known, with the exception of the compound, wherein R1 represents an isopropyl group. They can be prepared by the process given in U.S. Pat. No. 2,851,458. The preparation of the halo compound, wherein R1 stands for a formyl group, is described in the article Arzneim. Forsch., 12, 937-942 (1962), and that of the halo compound, wherein R1 means an acetyl group, is described in BE-P 645 602.
The compounds of the formula I have an effect on the central nervous system, and possess an especially valuable psychotropic action.
The biological effect of the compounds of the formula I was proved by the following tests:
1. Elevated Plus-Maze Test
The tests were carried out on male SPRD rats weighing 220 to 260 g. Each group of animal consisted of 8 to 10 pieces of rat. The substance to be examined or the vehicle (i.e. distilled water or a 0.4% solution of methylcellulose) was administered to the animals in a volume of 5 ml/kg as a solution or suspension per os 60 minutes prior to the test.
The elevated plus-maze consists of two open and two 40 cm wall enclosed arms of the same size (50xc3x9715 cm) arranged in the shape of a cross. The arms of the same type are opposite to each other. The junction of the four arms forms a central square area (15xc3x9715 cm). The apparatus is made of a wooden material elevated to a height of 50 cm and illuminated by a dim light from above. The essence of the method is that during the exploration of the apparatus, the animals spend considerably more time in the closed arms than in the open arms due to the natural fear from open space and height. Compounds having anxiolytic effect can significantly increase the time spent in the open arms as well as the number of entries into the open arms. The average values of these parameters were calculated, and, after statistical analysis, the minimum effective dose was determined for each compound [Pelow, S., Chopin, P., File, S. E., Briley, M.: Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat, J. Neurosci. Methods., 14, 149-167 (1985)].
The results obtained are shown in Table I. Diazepam [7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one] was used as the reference substance.
From Table I it can be seen that the compounds of the invention have the same or superiorxe2x80x94in some cases by orders of magnitude superiorxe2x80x94anxiolytic action than that of diazepam in the test.
2. Determination of the Spontaneous Motor Activity
For the experiments, male NMRI mice weighing 20 to 25 g were used. Each treatment group consisted of 10 mice. The substance to be examined or the vehicle (i.e. a 0.4% solution of methylcellulose) was administered to the animals in a volume of 20 ml/kg as a suspension per os 60 minutes prior to the test. The method gives a general information about the influence of the substance to be examined on the natural motion of animals, thus, the method reveals any sedative effect of the substance. In case of anxiolytics, the value of the anxiolytic effect depends on the presence or absence of the sedative action (the latter is desirable). For the experiments, an apparatus xe2x80x9cdigital motimeterxe2x80x9d having 10 measuring places was used. The motion of the animals was indicated by the interruption of three parallel beams of infrared light at each measuring place, and the interruptions were recorded by the apparatus. The activity of one animal was determined at each measuring place. From the results of the experiments, values of ID50 (i.e. the dose producing 50% of inhibition) were calculated [Borsy, I., Csxc3xa1nyi, E., Lxc3xa1zxc3xa1r, I., Arch. Int. Pharmacodyn., 124, 180-190 (1960); Stille, G., Leuener, H. and Eichenberger, E., II Farmaco Ed. Pr., 26 603-625 (1971)]. The data obtained are shown in Table II. Diazepam was used as the reference substance.
From Table II it can be seen that the compounds of the invention do not influence the motor activity of mice even in a dose that is higher by a factor of 14 than the ID50 value of diazepam used as the reference compound.
Summarized, it can be stated that the compounds of the invention have very significant anxiolytic effect, however, no sedative side effect can be observed even in a dose range that is higher by several orders than the anxiolytic dose.
The results of the above examinations suggest that the anxiolytic effect of the novel piperazinylalkylthiopyrimidine derivatives is more favourable than that of the benzodiazepines widely used in the therapy since the latter drugs are characterized by a high sedative side effect.
Thus, the novel piperazinylalkylthiopyrimidine derivatives of the formula I can be used as active ingredients in pharmaceutical compositions.
The pharmaceutical compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof and one or more conventional carrier(s).
The pharmaceutical compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.
The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
Pharmaceutical compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general.
Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington""s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).
The pharmaceutical compositions of the invention contain, in general, 0.1 to 95.0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt thereof. A typical dose for adult patients amounts to 0.1 to 1000 mg of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof, daily. The above dose can be administered in one or more portions. The actual dosage depends on many factors and is determined by the doctor.
The pharmaceutical compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically suitable acid addition salt thereof to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the literature, e.g. Remington""s Pharmaceutical Sciences mentioned above.
Preferably, the pharmaceutical compositions of the invention contain a piperazinylalkylthiopyrimidine derivative of the formula I, wherein
R1 represents a hydrogen atom, a dimethylamino(C1-4 alkyl) group or a C1-4 alkanoyl group,
R2 is as defined in connection with formula I,
n has a value of 2 or 3,
or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
The especially preferred pharmaceutical compositions of the invention comprise a piperazinylalkylthiopyrimidine derivative of the formula I, wherein
R1 represents a hydrogen atom or a dimethylamino(C1-4 alkyl) group,
R2 stands for a benzyl group substituted by a C1-4 alkoxy group or a fluoro atom,
n has a value of 2,
or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
Furthermore, the invention refers to a method for the treatment of diseases which comprises administering a therapeutically effective non-toxic amount of a piperazinylalkylthiopyrimidine derivative of the formula I or a pharmaceutically suitable acid addition salt thereof to a patient suffering from especially a disease of the central nervous system.
In addition, the invention includes the use of a piperazinylalkylthiopyrimidine derivative of the formula I or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition having anxiolytic effect.